Neoplasms

All Conditions

Mouth and Tooth Diseases

Rare Diseases

Carcinoma

Parotid Neoplasms

Salivary Gland Neoplasms

Mouth Neoplasms

Head and Neck Neoplasms

Mouth Diseases

Stomatognathic Diseases

Parotid Diseases

Salivary Gland Diseases

Oral Cancer

All patients will be offered radical adjuvant proton beam therapy to a dose of 60-66 Gray (Gy) in 30-33 fractions delivered Monday to Friday over 6-6.5 weeks.

Proton Beam Therapy

Romelie Rieu

Sally Falk

Chris Nutting

Proton Beam Therapy (PBT) is an advanced radiotherapy technique. There are two National Health Service (NHS) PBT treatment centres in the UK, one in Manchester and one in London. The NHS is committed to ensuring the best use of this limited resource by investigating which patients will benefit from PBT treatment.

Evaluative Commissioning in Protons (ECIP) is a programme of studies that explore the role of PBT for patients with different types of cancer. They are funded by NHS England. ECIP studies are not randomised studies, which means that all eligible patients will be offered proton therapy. Any patient in the United Kingdom (UK) can be referred, and for patients that need to travel far to their nearest centre, accommodation will be available.

The main benefit of PBT, compared with photon radiotherapy, is the predicted reduction in radiation dose to surrounding healthy tissues. With photon radiotherapy, some radiation passes beyond the target area, affecting healthy tissues and causing side-effects. With PBT, the radiation dose stops within the target area, causing less damage to surrounding tissues, and limiting side effects.

PRONTO is a study within the ECIP programme exploring whether PBT can reduce treatment side effects for patients with salivary gland cancers who need radiotherapy following surgery. Whilst radiotherapy is associated with good cancer control, it commonly causes problematic side-effects such as loss of taste and dry mouth. These can be permanent and can negatively affect someone's quality of life. PRONTO's main aim is to see if PBT can reduce the loss of taste following radiotherapy.

Participants in PRONTO will be closely monitored by the medical team and with questionnaires. The patient experience will be compared to what we would expect with standard photon radiotherapy.

Malignant parotid tumours are uncommon. Whilst 85% of salivary gland tumours originate in the parotid gland, only 20-25% of these are malignant, representing only 3-6% of head and neck cancers. This is about 650 patients/year in the UK.

Standard treatment for local disease is with surgical resection followed by adjuvant radiotherapy for patients with high-risk features. Local control and 5-year survival rates are good, at \>70% and \>80% respectively, but radiotherapy is associated with considerable toxicity. More than 70% of patients receiving photon therapy experience significant dysgeusia (taste loss/alteration). This can be permanent, is associated with weight loss, diminished appetite, dry mouth, and negatively impact on Quality of Life (QoL).

The putative benefit of proton beam radiotherapy (PBT) relates to its characteristic deposition in the body, which limits the radiation dose received by surrounding healthy tissues. We hypothesise that irradiating the post-operative parotid bed with PBT rather than Intensity Modulated Radiation Therapy (IMRT), will reduce the dose delivered to the Organs at Risk (OAR), in particular the oral cavity (OC), leading to a reduction in acute and long term taste loss/alteration. The advantageous physical properties of PBT may also improve other side effects including fatigue, mucositis, nausea \& vomiting and potentially hearing problems, as well as overall QoL.

Radiotherapy planning studies:

Radiation planning studies have repeatedly shown statistically significant reductions in the dose delivered to healthy tissues including: the oral cavity, brainstem, spinal cord, contralateral parotid, ipsilateral and contralateral submandibular glands and ipsilateral temporal lobe. In particular, radiotherapy doses to the oral cavity are significantly reduced, typically to below 10 Gray (Gy). No routinely contoured OAR or region of interest was consistently found to have higher doses planning with protons, although skin dose may be higher.

Clinical Trials:

Whilst there are no randomised control trials comparing protons and photons for this cohort. However, there is some clinical evidence that the use of PBT leads to clinically meaningful improvements in the side effects experienced by patients. One study compared acute toxicities between matched groups receiving either protons or photons, demonstrating statistically significant reductions in dysgeusia, fatigue, mucositis and nausea and vomiting in patients undergoing proton treatment. In other studies, PBT is associated with very low toxicity level, such as less than 30% of patients experiencing any dysgeusia. This compares favourably to photon experience, such as in the phase 3 randomised controlled trial 'A Multicentre Randomised Study of Cochlear Sparing Intensity Modulated Radiotherapy Versus Conventional Radiotherapy in Patients with Parotid Tumours' (COSTAR) where approximately 60% of patients reported dysgeusia in the Head \& Neck 35 (HN35) questionnaire at 1 year. The PRONTO study is powered to identify a clinically meaningful reduction in taste dysfunction of at least 20%.

Whilst late toxicities are also likely under-reported in the retrospective international data, the published literature to date is very reassuring. The mean dose to the ipsilateral temporal lobe is reportedly reduced, and reflected in low levels of subsequent headache, fatigue and/or memory change. Similarly, whilst poorly captured, low levels of hearing dysfunction or otalgia have also been reported following PBT.

There is no rationale at all that cancer outcomes, either local control or overall survival, will be worse with PBT than photon treatment. In studies to date, local control (approximately 95%) and overall survival (89%-96%) has been excellent, and comparative to known photon experience.

Evaluative commissioning study. This is a single arm, non-randomised study.

Investigating the Role of Adjuvant Proton Beam Therapy in Patients With Parotid Carcinoma

An Evaluative Commissioning Study to Investigate the Role of Adjuvant Proton Beam Radiotherapy in Patients With Localised Parotid Carcinoma

Taste dysfunction as recorded on the European Organisation for the Research \& Treatment of Cancer (EORTC) Head \& Neck 43 (HN43) patient reported questionnaire.

43 questions with a Likert scale of 1 - 4 Higher score may mean a worse outcome

Using the CTCAE toxicity grade Grades 1 - 5 Higher score may mean a worse outcome

Using the LENT-SOMA scale A multiple item scoring system composed of four domains; subjective, objective, management and analytic.

Grades 0-4 Higher score may mean a worse outcome

Using pure tone audiometry to measure hearing changes Loss of hearing may mean a worse outcome

Using the EORTC QLQ-C30 30 questions using a Likert scale of 1-4 Higher score may mean a worse outcome

Using the EORTC HN43 patient reported questionnaire 43 questions using a Likert scale of 1-4 Higher score may mean a worse outcome

Using the UW-QoL questionnaire Most questions are scored on a Likert scale, 0=worst, 100=best Lower score may mean worse outcomes

Using the GHABP questionnaire Possible values for response options (0=not applicable, 5=cannot manage at all) Higher score may mean worse outcomes

This will be measured as time to recurrence (measured in months from completion of treatment) and location of recurrence (within the primary nodal regional or distant spread)

This will be measured in months from completion of treatment to death

Number of patients referred to and participating in the study annually

Review the number of patients completing radiotherapy and the number of patients completing follow up on the study as per protocol.

Patients will be re-planned with photon radiotherapy, the dose distribution differences between the treatment proton plans and photon plans will be recorded in particular the dose to the oral cavity

Royal Marsden NHS Foundation Trust

University College London Hospitals

The Christie NHS Foundation Trust

Symptoms and General Pathology

Body Weight

Preoperative Assessment of Parotid Gland Neoplasms with:

* Clinical Evaluation;
* Fine Needle Aspiration Cytology;
* Multiparametric Magnetic Resonance Imaging.

Postoperative Collection of Final Histopathological Diagnosis

Multiparametric MRI evaluation includes Conventional MRI, Diffusion-Weighted MRI and Dynamic Contrast-Enhanced MRI

Multiparametric Magnetic Resonance Imaging

Ultrasound-Guided Fine Needle Aspiration Cytology

Fine Needle Aspiration Cytology

Patient's history and physical examination, reporting signs and symptoms suggestive of malignancy (pain, facial nerve weakness, fixation to skin and surrounding tissues, trismus, skin ulceration, lymphadenopathy, numbness, weight loss)

Clinical Evaluation

Final Diagnosis of the Disease from the Pathology Report after Surgical Resection of the Lesion

Final Histopathological Diagnosis

Davide Di Santo, MD

Parotid gland tumors are mostly treated surgically, but the extent of parotidectomy is decided upon preoperative work-up information. Preoperative management generally includes clinical evaluation, collection of a pathological sample, most often through fine-needle aspiration cytology (FNAC), and imaging. FNAC, despite its high sensitivity and specificity, has the drawback of an approximately 20 per cent rate of nondiagnostic or indeterminate result. Magnetic Resonance Imaging (MRI) provides the best morphological description of the lesion, which is helpful to the surgeon for the planning of the intervention. Recently, advanced functional techniques have been introduced, in association to the conventional morphologic ones: diffusion-weighted imaging (DWI) and dynamic contrast-enhanced imaging (DCEI) demonstrated the ability to provide information about the possible histological origin of parotid lesions. Multiparametric MRI (mp-MRI) comes from the combination of anatomical and functional sequences.

The Authors postulate that mp-MRI evaluation may be able to provide information not only about the extension of the lesion, but also about histology, with a high accuracy, at least comparable to ultrasound-guided FNAC.

In the present study, the Authors aim to define the value of FNAC and mp-MRI in the preoperative management of parotid gland tumors, comparing their success intended as the capability of the exam to be both diagnostic and accurate in formulating the correct histological suspect of malignancy.

Participants are patients affected by parotid gland neoplasms, candidates for surgical resection. The lesion will preoperatively be assessed with both clinical evaluation, ultrasound-guided FNAC and mp-MRI in our Institution. Mp-MRI includes conventional sequences, DWI and DCEI; its interpretation will allow the definition of the suspect histology. FNAC and mp-MRI suspects will be compared to the final histopathological report after surgical removal of the neoplasm.

The study considers a total of 100 patients, of whom 50 are analyzed retrospectively (being already operated after obtaining both FNAC and mp-MRI preoperatively) and the remaining 50 to be enrolled prospectively.

Participants affected by parotid gland neoplasms are evaluated by an ear, nose and throat surgeon in our hospital, who defines the indication to surgical removal.

Preoperative management includes:

* Clinical Evaluation: participant's history and physical examination are collected. Participants are asked for the presence of pain, facial nerve weakness, fixation to skin and surrounding tissues, trismus, skin ulceration, lymphadenopathy, numbness, B symptoms.
* FNAC: it is always performed under US guidance in our Department of Radiology, and subsequently analyzed by a cytopathologist in our Department of Pathology. The same sampling technique is always employed. After skin disinfection, a 23-gauge needle attached to a syringe is inserted into the lesion and moved inside it to obtain enough cytological material. The material is subsequently expelled onto a glass slide, and the smear is prepared between two glass slides and fixed. The procedure is repeated two to three times to reduce the probability of nondiagnostic results.
* mp-MRI: MRI scans are conducted using a 1.5-T imager (Philips Health-care, DA Best, The Netherlands) with a head and neck array coil. The MRI study protocol consists of localizer sequences in transversal, sagittal and coronal planes followed by two axial T2 weighted images: a T2 Turbo Spin-Echo (repetition time -TR-: 4465, echo time -TE-: 80, section thickness: 3mm, intersection gap: 0.3mm) centered on parotid glands and a T2 MV sequence for lymph nodes identification (TR: 3000, TE: 83, section thickness: 4mm, intersection gap: 0.4mm). Then axial T1 weighted images are obtained (TR: 571, TE: 16, section thickness: 3 mm, intersection gap: 0.3mm). Coronal T1, T2 and STIR images are subsequently obtained. Thereafter, DWI is performed by using a multisection spin-echo singleshot echoplanar sequence in the transverse plane (TR: 2800, TE: 160, 20 - 25cm field of view, 92 x 90 matrix, 3mm section thickness). Sensitizing diffusion gradients are applied sequentially in the x, y, and z directions with b values of 0, 500, and 1000 sec/mm2. ADC maps are generated. After detecting the mass in the morphological images, The Radiologist identifies corresponding slice position for a T1 weighted FLASH sequence (TR: 30, TE: 4.6) in the transversal plane, used for DCEI. Each patient receives intravenous contrast injection (weight-adapted dosage, 0.1ml Gadolinium per Kilogram body weight) with a flow rate of 2ml/second using a power injector, followed by a 20ml saline flush. The contrast agent application and the T1-weighted FLASH sequence are started simultaneously. MR images are sequentially obtained at 5sec intervals for 360sec. After DCEI, postcontrast T1 weighted spin echo images are obtained, with the parameters similar to those of the pre-contrast imaging. A region of interest (ROI) for signal intensity measurement is drawn manually avoiding the vessels and necrotic or cystic portions of the tumors. Thereafter, the Radiologist plots the average signal intensity within the ROI against time, and a Time Intensity Curve (TIC) is constructed, using a dedicated software (Philips Intellispace Portal). The ROI can be identified with an adequate accuracy only for tumors with a minimum diameter of 1cm; therefore for smaller lesions a mp-MRI analysis is not possible. TICs are constructed as follows: Time to peak (Tpeak) is manually positioned by the Radiologist in the first value of the curve in which the signal intensity (SI) reached the 90% of the difference between the maximum (SImax) and the starting (SIpre) signals: Tpeak \> 0.9 (SImax - SIpre) + SIpre. Washout Ratio (WR) is calculated at 300sec (SIend) and expressed as a percentage, using the following equation: WR = \[(SImax - SIend) / (SImax - SIpre)\] x 100 (%). TICs are defined as follows: Type A: Tpeak \> 120sec (gradual enhancement, ascending plateau); Type B: Tpeak ≤ 120sec and WR ≥ 30% (early enhancement, early washout); Type C: Tpeak ≤ 120sec and WR \< 30% (early enhancement, late washout); Type D: flat curve (vacillation of the curve around the low signal level may be observed due to imaging artifacts).

Interpretation of preoperative management findings aims to label each case as "benign" or "malignant", and is performed as follows:

* Clinical Evaluation: malignancy is suspected if any of pain, facial nerve weakness, fixation to skin and surrounding tissues, trismus, skin ulceration, lymphadenopathy, numbness, B symptoms is present.
* FNAC results were classified as: "benign" if a specific histologically benign diagnosis was made, if the report stated "no evidence of malignancy", or if only benign diagnoses were listed in the differential; "malignant" if a specific histologically malignant diagnosis was made, if malignant cells were identified, if the report stated "suspicious for malignancy" or "suspicious for lymphoproliferative disorder". The decision to consider as malignant also reports stating "suspicious for" comes from the observation that surgeons would manage these lesions as malignant anyway; "indeterminate" if, despite the presence of a cytologically adequate sample, the pathologist was not able to define the benign or malignant nature of the lesion; "nondiagnostic" if the pathological sample was insufficient or did not contain enough meaningful material.
* Conventional MRI results are classified as "malignant" if: presence of infiltration of surrounding non-glandular structures (including the facial nerve) is identified; presence of suspect metastatic lymph nodes is identified; the tumor is characterized by low signal on T2-weighted images and displays ill-defined borders. All other cases were classified as "benign".
* Multiparametric MRI results are recorded, and interpreted according to a stepwise approach. The first step of mp-MRI interpretation is the evaluation of conventional MRI findings. If the tumor presented features undoubtedly indicating a malignant origin (infiltration of contiguous non-glandular structures - including the facial nerve - or evidence of lymph node metastases), the lesion is immediately labeled as "malignant" at mp-MRI. The third category used to define malignant nature at conventional MRI evaluation, such as low signal on T2-weighted images and ill-defined borders is not considered as undoubtedly indicating malignancy, and further steps of mp-MRI evaluation are performed. After conventional MRI evaluation, advanced MRI techniques are used. The second step includes DWI with ADC maps generation and measurement. Depending on the ADC value, three main categories are identified: 1. tumors with extremely low ADC value (\< 0.6 x 10\^-3 mm2/sec); 2. tumors with low or intermediate ADC value (≥ 0.6 x 10\^-3 mm2/sec and ≤ 1.4 x 10\^-3 mm2/sec);
* tumors with high ADC value (\> 1.4 x 10\^-3 mm2/sec). The third step is the construction of a TIC using DCEI. Findings obtained with both DWI and DCEI are combined and interpreted as follows: A. high ADC value (\> 1.4 x 10\^-3 mm2/sec) and TIC type A, B (not plausible) or C are most often suggestive of a Pleomorphic Adenoma (PA), but also of myoepithelioma. Due to the rarity of myoepithelioma and to the fact that its surgical treatment is essentially the same of PA, this eventuality is not considered. TIC type B is not considered a plausible possibility, as this finding is very rarely reported in PAs. In such cases, a hemorrhagic complication after a recently performed FNAC in a Warthin Tumor (WT) should be considered. Tumors in this category are labeled as "benign", with suspected histology of PA; B. high ADC value (\> 1.4 x 10\^-3 mm2/sec) and TIC type D can be referred to cystic lesions. Cysts are characterized by very high ADC values, being composed of fluid or mucinous content. Tumors in this category are labeled as "benign", with suspected histology of cystic lesion; C. low or intermediate ADC value (≥ 0.6 x 10\^-3 mm2/sec and ≤ 1.4 x 10\^-3 mm2/sec) and TIC type A or C are typical of malignant epithelial tumors, but also of some atypical adenomas (cellular adenomas, basal cell adenomas). In an attempt to reduce the number of false negative results, tumors in this category are labeled as "malignant". No specific tumor histology can be suspected, due to the large overlap of findings and the high number of parotid gland malignant histotypes; D. low or intermediate ADC value (≥ 0.6 x 10\^-3 mm2/sec and ≤ 1.4 x 10\^-3 mm2/sec) and TIC type B are typical of WTs. Tumors in this category are labeled as "benign", with suspected histology of WT; low or intermediate ADC value (≥ 0.6 x 10\^-3 mm2/sec and ≤ 1.4 x 10-3\^mm2/sec) and TIC type D are not plausible, as TIC type D is typical of cysts, which are characterized by very high ADC values. In such cases, one should consider the possibility of repositioning the ROI, as this finding may be related to positioning of the ROI in a necrotic or cystic portion (therefore not informative) of a parotid tumors; E. extremely low ADC value (\< 0.6 x 10\^-3 mm2/sec) and TIC type A (not plausible), B or C are suggestive of parotid gland lymphomas. Tumors in this category are labeled as "malignant", with suspected histology of lymphoma; F. extremely low ADC value (\< 0.6 x 10\^-3 mm2/sec) and TIC type D are suggestive of lipomas. Lipomas display typical very low ADC values. Tumors in this category are labeled as "benign", with suspected histology of lipoma; G. mp-MRI IS considered "indeterminate" if the exam is unable to reliably measure ADC or construct a TIC, due to a very recently performed FNAC (less than two weeks) with reported complications (clinical evidence of infection or conventional MRI evidence of intralesional hemorrhage), or intense movement artifacts.

Study power analysis:

The number of participants to be treated is decided taking into account the paired design of the study, to detect any difference in the percentage of success (intended as the capability of the diagnostic test to be diagnostic and to correctly identify malignant tumors) between the two tests (FNAC and mp-MRI), assuming a percentage of participants for whom mp-MRI has success while FNAC does not of 20%, a percentage of participants for whom FNAC has success while mp-MRI does not of 5%, a power of 80% and an alfa error of 5%. These percentage strictly depend on the expected rate of non success due to indeterminate or nondiagnostic results of the tests. Therefore, we defined to be 100 participants the number to be treated.

Statistical analysis:

Number of indeterminate and nondiagnostic results, sensitivity, specificity, positive predictive value, negative predictive value and accuracy of Clinical Evaluation, FNAC, conventional MRI and mp-MRI will be reported. The comparison between success of respectively FNAC and mp-MRI will be investigated with the McNemar test. SPSS software (IBM Corporate, US) will be used. P will be considered to be significant if \< 0.05.

Multiparametric Magnetic Resonance Imaging Versus Fine Needle Aspiration Cytology for Parotid Gland Neoplasms

Accuracy of Multiparametric Magnetic Resonance Imaging Versus Fine Needle Aspiration Cytology in the Preoperative Work-Up of Parotid Gland Neoplasms

No consent from the participants to share data

Success is intended as the capability of the diagnostic test (Multiparametric MRI and Fine Needle Aspiration Cytology) to be diagnostic (i.e. to make a diagnosis of benignity or malignancy) AND to correctly identify malignant tumors, compared to the final histopathological report

Diagnostic accuracy of the test (clinical evaluation, fine needle aspiration cytology, conventional MRI, multiparametric MRI) is defined as the number of malignant lesions with "malignant" results in addition to benign lesions with "benign" results as a percentage of the total number of lesions

Diagnostic accuracy of the test (Multiparametric MRI and Fine Needle Aspiration Cytology) is intended as the capability to preoperatively identify the histopathology of the tumor (pleomorphic adenoma, warthin tumor, carcinoma, lymphoma)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Investigating the Role of Adjuvant Proton Beam Therapy in Patients With Parotid Carcinoma	NCT06421649	Parotid Cancer	Proton Beam The...	18 Years -	The Christie NHS Foundation Trust
Investigating the Role of Adjuvant Proton Beam Therapy in Patients With Parotid Carcinoma	NCT06421649	Parotid Cancer	Proton Beam The...	18 Years -	The Christie NHS Foundation Trust
Multiparametric Magnetic Resonance Imaging Versus Fine Needle Aspiration Cytology for Parotid Gland Neoplasms	NCT03849482	Parotid Neoplas... Parotid Cancer	Multiparametric... Fine Needle Asp... Clinical Evalua... Final Histopath...	18 Years -	IRCCS San Raffaele

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